Vectors based on the DNA viruses, adenoviruses, and adeno-associated virus (AAV), have shown promise for in vivo gene transfer. Adenoviral vectors have been the mainstay for experimental and clinical application of in vivo gene transfer. The efficiency of gene transfer has been high with adenoviruses; however, problems of vector instability and vibrant immune response have limited their utility. Attempts to further disable recombinant adenoviruses have shown promise in overcoming some of these limitations. More recently, AAV has shown promise for efficient, stable, and safe application to muscle and liver-directed gene transfer. It appears AAV can evade problematic immune response to the transgene product. In addition, interesting data have emerged regarding the potential utility of adenoviruses fully deleted of all open reading frames. This P01 application will build on the known biology of AAV and fully deleted adenoviruses to a variety of targets relevant to cardiovascular diseases. Project 1 by Dr. James Wilson will study the biology of transduction and immunology of AAV in the context of liver and muscle. More focused studies will be performed with fully deleted adenoviral vectors. Information gained from Project 1 will be transferred to disease- based applications in Projects 2 and 3. Dr. Lee Sweeney (Project 2) will use gene transfer to target cells to cardiac muscle. He will study the pathogenesis of family hypertrophic cardiomyopathy and develop genetic treatments for inherited and acquired cardiomyopathy Dr. Rader (Project 3) will evaluate the consequence of apoprotein expression in atherosclerosis using the vectors developed in Project 1. Data emerging from Projects 2 and 3 will feedback to the basic vector biology performed in Project 1. Two existing cores of the Institute for Human Gene Therapy, the Vector Core and Cell Morphology will support work in the three projects.